A recent study uncovers a new mechanism by which colorectal cancer (CRC) evades the immune system and resists PD-L1 blockade. Researchers found that the protein G3BP2 undergoes acetylation at lysine 76 (K76), a modification added by the acetyltransferase p300 and removed by the deacetylase HDAC6.
This acetylation stabilizes PD-L1 mRNA through interaction with PABPC1, increasing PD-L1 protein on tumor cells. Elevated PD-L1 suppresses cytotoxic T cells, allowing tumors to grow unchecked. Analysis of 36 CRC patients showed that high G3BP2-K76 acetylation levels were associated with resistance to pembrolizumab and reduced CD8+ T-cell infiltration.
To counter this, researchers developed a peptide inhibitor, K76-pe, which selectively blocks G3BP2-K76 acetylation. In mouse models, K76-pe lowered PD-L1 expression and restored sensitivity to anti-PD-L1 therapy, slowing tumor growth.
Targeting the G3BP2-K76 acetylation axis offers a promising strategy to convert “cold,” immunotherapy-resistant colorectal tumors into “hot,” treatment-responsive ones, potentially improving outcomes for patients who do not respond to current immune checkpoint therapies.